Abstract

Objectives The goal of this analysis was to determine the association between intraprocedural complications and clinical outcomes among patients with high-risk non–ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI).

Background Among patients undergoing PCI for NSTEACS, the relationship between intraprocedural complications and clinical outcomes, independent of epicardial and myocardial perfusion, has not been well characterized.

Methods The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) trial enrolled 9,406 patients with high-risk NSTEACS undergoing an early invasive strategy. Of these, 1,452 underwent angiographic assessment in an independent core laboratory and did not have a myocardial infarction (MI) between enrollment and angiography. We assessed the relationship between abrupt closure, loss of side branch(es), distal embolization, and no-reflow phenomenon and 30-day clinical outcomes in these patients.

Results Of the patients, 166 (11.4%) experienced an intraprocedural complication. Baseline clinical characteristics were similar between patients who did and did not have complications. The 30-day composite of death or MI was significantly higher among patients with an intraprocedural complication (28.3% vs. 7.8%, odds ratio [OR]: 4.68, 95% confidence interval [CI]: 3.2 to 7.0, p < 0.001). Individually, both mortality (3.0% vs. 0.9%, OR: 3.60, 95% CI: 1.2 to 10.5, p = 0.019) and MI (27.1% vs. 7.4%, OR: 4.66, 95% CI: 3.1 to 7.0, p < 0.001) were significantly increased. After adjusting for differences in post-PCI epicardial and myocardial perfusion, the association with 30-day death or MI remained significant.

Conclusions Among high-risk NSTEACS patients undergoing an invasive strategy, the incidence of intraprocedural complications is high, and the occurrence of these complications is associated with worse clinical outcomes independent of epicardial and myocardial perfusion.

Periprocedural myocardial infarction (MI), which has been independently associated with a higher incidence of subsequent major adverse cardiovascular events, is common among patients with non–ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI) (1–5). However, both the definition and clinical significance of periprocedural MI are difficult to evaluate, as many patients with ACS have elevated biomarkers at the time of PCI related to their index event. Intraprocedural complications, such as loss of a coronary artery side branch, abrupt closure, distal embolization, and the no-reflow phenomenon can be objectively defined and occur in patients both with and without biomarker elevation at presentation.

The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) trial enrolled 9,406 evaluable patients with high-risk NSTEACS undergoing an early invasive strategy (6). The goal of this analysis was to determine the incidence of intraprocedural complications and to determine whether these complications were associated with adverse cardiovascular events independent of epicardial and myocardial perfusion at the completion of the procedure. An additional goal was to determine whether the intraprocedural complications were associated with adverse outcomes independent of the patient's baseline troponin status prior to PCI.

Methods

Patient population

EARLY ACS enrolled patients with high-risk NSTEACS intended to undergo an early invasive treatment strategy. The patient population has been previously described (6,7). Briefly, patients who were at least 18 years of age were eligible if they had cardiac ischemia at rest lasting for at least 10 min and occurring within 24 h before study entry, with a planned invasive strategy no sooner than the next calendar day after randomization. They had to be enrolled within 8 h (12 h after a protocol amendment during the trial) of arrival in the emergency department. Patients were considered to have a high-risk condition if they met 2 or more of the following criteria: ischemic changes on electrocardiography (ST-segment depression of 0.1 mV or more, or transient [<30 min] ST-segment elevation of 0.1 mV or more in 2 or more contiguous leads), troponin or creatine kinase-myocardial band (CK-MB) above the local laboratory upper limit of normal, and an age ≥60 years. A protocol amendment during enrollment permitted the enrollment of patients who were between the ages of 50 and 59 years if they had elevated levels of troponin or CK-MB and documented coronary, cerebrovascular, or peripheral artery disease.

Study procedures

Patients in EARLY ACS were randomized to either double-bolus eptifibatide plus infusion or matching placebo, in addition to standard antithrombotic therapy, including aspirin, clopidogrel, and anticoagulant. Before PCI, investigators could opt to use a “PCI active kit” if they felt a glycoprotein inhibitor was needed during PCI. In addition, investigators could request a “bailout eptifibatide” kit if during PCI, the subject had a thrombotic complication and the PCI active kit had not been administered.

Angiographic cohort

For the EARLY ACS angiographic substudy, investigators were asked to send copies of their patients' angiograms to the PERFUSE Angiographic Core Laboratory at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Sites were urged to submit angiograms for this substudy. The goal was to obtain 2,000 angiograms for analysis. From this population, patients who did not have an MI between enrollment and angiography were included in the current analysis. An MI between enrollment and angiography was defined as elevation of cardiac biomarkers above the upper limit of normal following enrollment and before angiography when the first set of cardiac biomarkers was normal.

Angiographic analysis

All angiograms were evaluated independently by trained reviewers who were blinded to treatment assignment, clinical and procedural data from the case report form, and clinical outcomes. Angiograms were evaluated for epicardial coronary flow using the Thrombolysis In Myocardial Infarction (TIMI) flow grade (TFG) and the corrected TIMI frame count (cTFC) (8,9). Myocardial perfusion was evaluated using the TIMI myocardial perfusion grade (TMPG) (10). Angiographic perfusion score was calculated as previously described (11). Quantitative coronary angiography was also used to determine the degree of coronary stenosis. Intraprocedural complications were defined as transient or sustained loss of side branch, abrupt closure, distal embolization, and the no-reflow phenomenon.

Loss of a side branch was defined as the development of TFG 0 or 1 in a side branch that was >1.5 mm in diameter before the procedure and that was initially patent with TFG 2 or 3. Distal embolization was defined as the appearance of an abrupt cutoff in the distal vessel following PCI. No-reflow was defined as markedly delayed flow down the artery with minimal residual stenosis. Abrupt closure was defined as shown in Table 1. The thrombus grade was defined as described by Gibson et al. (12).

Statistical analysis

Baseline characteristics, angiographic findings, and clinical outcomes were summarized using means with standard deviations for continuous variables and frequencies for categorical variables. The Wilcoxon rank sum test was used for comparisons of continuous variables, and the chi-square or Fisher exact test was used for comparisons of categorical variables. Odds ratios (ORs) with 95% confidence intervals (CIs) obtained using logistic regression modeling were used to describe the association of intraprocedural complications with the 30-day composite of death or MI (both spontaneous and periprocedural) and secondarily with death and MI separately. Adjusted comparisons considered post-PCI epicardial and myocardial perfusion as described by TFG and TMPG. Additionally, we assessed the association of intraprocedural complications with clinical outcomes after adjusting for pre-PCI troponin status as reported by the individual sites, on the basis of local laboratory findings. The p values are reported using the log-rank test for the Kaplan-Meier failure curves. p Values (2-tailed) <0.05 were considered statistically significant. No adjustments were made for multiple comparisons. All analyses were performed using Stata/IC, version 10.1 (StataCorp, College Station, Texas).

Results

Patient population and baseline characteristics

Of 9,406 EARLY ACS patients, 1,452 did not have an MI between enrollment and angiography, and had angiograms available for analysis at an independent core laboratory. Baseline clinical characteristics comparing patients who had angiograms available for analysis and those who did not are shown in Table 2. Patients who had angiograms available for analysis were, on average, younger, more likely to be male, have dyslipidemia and elevated troponin at baseline, and less likely to have a TIMI risk score >2, present to a tertiary care hospital, or have a prior MI, hypertension, creatinine clearance <50 ml/min, or be in Killip class II, III, or IV heart failure at presentation. There were also differences in the use of eptifibatide, antithrombotic therapy, and antiplatelet therapy.

Of the 1,452 patients, 166 (11.4%) had at least 1 intraprocedural complication (49.4% loss of side branch, 42.2% abrupt closure, 30.3% distal embolization, 3.6% no-reflow; these categories are not mutually exclusive). Among patients with loss of a side branch, 22.0% were rescued with PCI. Of the patients with abrupt closure, 71.4% had transient closure and 27.1% had sustained closure.

The baseline characteristics of patients with and without intraprocedural complications are shown in Table 3. The groups were generally similar, except that patients with an intraprocedural complication tended to have diabetes mellitus (p = 0.07) more often and less prior PCI (p = 0.07). Troponin elevation as reported by the individual sites using local laboratory findings before angiography was similar between groups. The use of bailout eptifibatide was significantly higher among those with an intraprocedural complication.

Angiographic characteristics

Angiographic findings before PCI are shown in Table 4. Patients who had an intraprocedural complication had significantly worse pre-PCI TFG, higher mean cTFC, and higher TMPG. In addition, patients who experienced an intraprocedural complication had more severe stenoses and were also more likely to have a thrombus present.

Kaplan-Meier estimates of the rate of the composite of death and myocardial infarction (MI) (A), mortality (B), and myocardial infarction (C) comparing patients with and without intraprocedural complications (loss of side branch, abrupt closure, distal embolization, and the no-reflow phenomenon). OR = unadjusted odds ratio.

As the number of intraprocedural complications increased, the rate of the composite of death or MI increased from 7.6% (97 of 1,275) for patients with no complications to 24.8% (32 of 129) for patients with 1 complication to 38.9% (14 of 36) among patients with more than 1 intraprocedural complication (p < 0.001 for all comparisons) (Fig. 2).

The analysis was then restricted to patients with a patent infarct-related artery before PCI (TFG: 2 or 3, n = 1,152). The incidence of the composite of death or MI at 30 days was significantly higher among patients who experienced an intraprocedural complication (32.8% vs. 7.8%, OR: 5.73, 95% CI: 3.7 to 8.9, p < 0.001). The same held true when evaluating death (4.2% vs. 0.6%, OR: 7.51, 95% CI: 2.3 to 25.0, p = 0.001) and MI (31.1% vs. 7.6%, OR: 5.52, 95% CI: 3.5 to 8.7, p < 0.001) alone.

Adjusted outcomes according to occurrence of intraprocedural complications

After adjusting for differences in parameters of epicardial and myocardial perfusion following PCI as well as elevated troponin before PCI, the relationship between intraprocedural complications and the composite of death or MI at 30 days remained significant (adjusted OR [ORadj]: 3.56, 95% CI: 2.2 to 5.7, p < 0.001). The same held true for MI (ORadj: 3.58, 95% CI: 2.2 to 5.8, p < 0.001) alone, but the difference in mortality alone was directionally similar but no longer statistically significant (ORadj: 2.30, 95% CI: 0.5 to 10.2, p = 0.27).

Discussion

Intraprocedural complications occurred in more than 11% of patients with NSTEACS undergoing an early invasive strategy. Such complications were associated with a more than 4-fold increase in the risk of death or spontaneous or periprocedural MI at 30 days, even after adjusting for differences in post-PCI epicardial flow and myocardial perfusion and elevated troponin before PCI. Further, the greater the number of intraprocedural complications, the worse were the clinical outcomes. Among patients with a patent artery before PCI, the relationship between intraprocedural complications and the risk of 30-day death or MI remained significant. Moreover, there was a strong relationship between intraprocedural complications and 30-day outcomes among patients with and without elevated troponin before PCI. These results from a blinded angiographic core laboratory build upon results of previous analyses using site investigator–reported angiographic complications and clinical outcomes, and suggest a potential role for intraprocedural complications as an intermediate endpoint in clinical trials (13).

Elevated cardiac biomarkers following PCI in patients who already have elevated biomarkers before the procedure may represent the consequence of myocardial injury and biomarker release both before and following the procedure. The relative contribution of pre-procedure biomarker release can therefore confound the interpretation of biomarker elevations following PCI, including the assessment of the association of procedure-related biomarkers with subsequent ischemic outcomes. The present study indicates that independent of troponin elevation before PCI, the occurrence of a complication during the procedure is associated with an increased risk of adverse events during follow-up, including mortality.

This angiographic endpoint also provides additional prognostic information independent of epicardial flow and downstream myocardial perfusion. Indeed, closure of side branches may not be counted as an adverse outcome using traditional measures of angiographic success, which focus exclusively on outcomes in the parent artery or distal to the parent artery. Cardiovascular magnetic resonance imaging data indicate that hyperenhancement consistent with myonecrosis may occur not only distal to the parent artery, presumably due to embolization, but also adjacent to the parent artery in the vicinity of branches (14). Side branches are frequently present at the site of culprit lesions in patients with ACS (15), and in this setting, side branch occlusion may occur in more than 20% of patients, most commonly following stent dilation (15,16). In the present study, about one-quarter of occluded side branches were successfully recanalized with PCI.

Both patients with and without troponin elevation before PCI had a significantly higher composite of death and MI. Patients without troponin elevation before PCI who had an intraprocedural complication had a much higher increase in the risk of death and MI than those with elevation of cardiac biomarkers before PCI. This may be the play of chance, as there were far more patients with normal cardiac biomarkers before PCI. However, 1 potential reason for this finding is that patients who are already having an MI have less myocardium at risk in the downstream territory, and patients who have a periprocedural MI when no MI was ongoing lose more myocardium.

Abrupt closure occurs in about 3% to 6% of PCIs and is more common after balloon angioplasty than stent implantation (17,18). In prior studies, abrupt closure was associated with periprocedural MI in approximately 5% of patients and an in-hospital mortality of approximately 2% (17). In the present study, abrupt closure was transient in three-quarters of patients, having resolved by the end of the case.

Distal embolization is common among patients undergoing PCI, especially during ACS. Predictors of distal embolization are largely related to plaque burden and constitution. A larger necrotic core, the presence of thrombus, a thin fibrous cap atheroma, and large lipid arc size detected via intravascular ultrasound and optical coherence tomography have been strongly associated with a higher incidence of distal embolization and the no-reflow phenomenon (18–20). The occurrence of no-reflow in contemporary treatment of ACS patients may be as high as 35%, although its incidence is significantly higher among ST-segment elevation MI patients undergoing primary PCI (21). It is likely related to a combination of distal embolization, ischemia-related injury, and reperfusion-related injury (21), and it has been strongly related to adverse clinical outcomes (22–24).

Prior clinical outcomes studies among patients with stable coronary artery disease and ACS undergoing PCI have focused largely on a periprocedural rise in cardiac biomarkers as a surrogate outcome. However, particularly among patients with NSTEACS, increased cardiac biomarkers measured following PCI may be the result of ongoing myocardial necrosis that occurred as a consequence of their presenting ACS itself rather than as a result of the PCI. Intraprocedural complications are objective, definable outcomes that the current study suggests are clinically relevant.

Study limitations

Several limitations are acknowledged. This is a small subset from a randomized controlled trial, and the population may be inherently different from a real-world population. Patients included in this analysis were from a convenience sample of angiograms, and so were significantly different from the population enrolled in EARLY ACS as a whole. Although this does not alter the significant relationship between complications and outcomes, it is an acknowledged limitation of the study. The patients in the present study were high-risk NSTEACS patients, and it is unknown whether these findings would apply to patients with stable coronary disease undergoing elective procedures or those with ST-segment elevation MI. Because the groups we compared were formed on the basis of whether or not complications occurred, and patients were treated according to local standard of care, there were likely inherent baseline differences between the cohorts, due to unmeasured confounders. These differences may have led to the occurrence of intraprocedural complications or may have led to differences in treatment strategies after the procedure that influenced outcomes. In particular, physician behavior, which may be dictated by any of a number of factors, including regional or local practice patterns or operator, patient, or lesion characteristics, may have been important considerations but were not measured. Therefore, these findings should be validated in other cohorts.

Conclusions

Among patients with NSTEACS undergoing an early invasive strategy, intraprocedural complications (loss of side branch, abrupt closure, distal embolization, and the no-reflow phenomenon) occurred in more than 11% of patients and were associated with a more than 4-fold increase in the composite of death or MI at 30 days, even after adjusting for differences in post-PCI TFG and TMPG and elevated troponin before PCI. Intraprocedural complications are objective, definable outcomes that should be considered as intermediate endpoints in future clinical trials.